Mechanism of Action of Botulinum Toxin (Botox)
Botox mediates hydrolysis of synaptic terminal proteins, specifically cleaving SNARE complex proteins (SNAP-25, VAMP/synaptobrevin, and syntaxin) that are essential for acetylcholine release from presynaptic motor neurons. 1
Molecular Mechanism
Botulinum toxin functions as a zinc-endopeptidase that systematically disrupts neurotransmission through the following sequence: 1
Heavy chain binding: The toxin's heavy chain (approximately 100,000 daltons) binds to peripheral cholinergic nerve terminals, including neuromuscular junctions and postganglionic parasympathetic nerve endings 1
Receptor-mediated endocytosis: After binding, the toxin is internalized into the presynaptic neuron through receptor-mediated endocytosis 1, 2
Translocation and proteolytic cleavage: The toxin translocates to the cytosol where its light chain (approximately 50,000 daltons) cleaves specific SNARE complex proteins required for synaptic vesicle fusion 1, 3
Inhibition of acetylcholine release: This proteolytic cleavage prevents synaptic vesicles from fusing with the presynaptic membrane, thereby blocking acetylcholine release and preventing neurotransmitter exocytosis 1, 4, 3, 5
Serotype-Specific Targets
Different botulinum toxin serotypes cleave distinct proteins or different sites on the same protein: 3
- Type A and E: Both cleave SNAP-25 but at different bonds, contributing to their dissimilar durations of muscle relaxation 3
- Type B: Cleaves VAMP/synaptobrevin 3
- The specific cleavage sites determine the clinical potency and duration of effect, with type A producing the most severe and prolonged paralysis 1
Clinical Consequence
The characteristic descending flaccid paralysis results from blocking acetylcholine transmission at the neuromuscular junction through inhibition of presynaptic acetylcholine release, not through postsynaptic receptor effects or neuronal hyperpolarization 1
Recovery occurs over weeks to months only after sprouting of new nerve terminals, as the proteolytic damage to SNARE proteins is irreversible 1, 6
Why Other Options Are Incorrect
- Acetylation of mitochondrial proteins: No evidence supports this mechanism 1, 3
- Activation of presynaptic receptors: Botox binds but does not activate receptors; it enters cells to cleave intracellular proteins 1, 2
- Hyperpolarization of inhibitory neurons: The toxin does not alter membrane potential; it prevents vesicle fusion 1, 3
- Inhibition of synaptic neurons: While this describes the clinical effect, the molecular mechanism is specifically protein hydrolysis, not direct neuronal inhibition 1, 3